In lesions of white matter in Multiple Sclerosis (MS), remyelination occurs to a limited extent, but the disease progresses and remyelination fails, at least in part, due to a shortage of oligodendrocyte (OL) progenitors (13). Therefore, therapies that would stimulate the proliferation and differentiation of OLs would be of tremendous benefit for patients afflicted with MS or other demyelinating diseases. The rationale behind the experiments in this proposal is based on the fact that significant numbers of slowly dividing OL precursors remain in the adult brain of both rodents and humans, and some of these cells mature into oligodendrocytes. Amplifying their numbers would produce a reservoir of immature cells that could re-populate and re-myelinate the denuded axons that are produced in demyelinating diseases such as MS. Furthermore, recent in vitro evidence suggests that differentiated oligodendrocytes can be induced to de-differentiate and proliferate (6). Numerous growth and trophic factors have been identified that promote the proliferation, differentiation or survival of OLs and their progenitors. Therefore, the long-term goal of this research program is to identify novel combinations of cytokines and growth factors that can be developed into therapeutic treatments for patients with demyelinating diseases. The immediate goal of this project is to test the hypothesis that combinatorial administration of CNTF and FGF-2 will induce production of OLs in the adult. To test our central hypothesis, we will pursue five specific aims to demonstrate that: 1) CNTF/FGF-2 enhances proliferation of OL progenitors, 2) CNTF enhances FGF-2 induced proliferation of differentiated OLs, 3) stimulation of the IGF-type I receptor is required for CNTF/FGF-2 mediated mitogenicity, 4) CNTF induces expression of receptors for FGF-2 and IGF-I on OLs or OL progenitors both in vitro and in vivo, and 5) co-administration of CNTF and FGF-2 in vivo will induce OL production in normal and demyelinated adult white matter and will promote remyelination of a focal demyelinating lesion.